The Crystal Structures of TrkA and TrkB Suggest Key Regions for Achieving Selective Inhibition

被引：111

作者：

Bertrand, T. ^{[1
]}

Kothe, M. ^{[3
]}

Liu, J. ^{[3
]}

Dupuy, A. ^{[1
]}

Rak, A. ^{[1
]}

Berne, P. F. ^{[2
]}

Davis, S. ^{[3
]}

Gladysheva, T. ^{[3
]}

Valtre, C. ^{[2
]}

Crenne, J. Y. ^{[2
]}

Mathieu, M. ^{[1
]}

机构：

[1] Sanofi, Dept Struct Design & Informat, F-94403 Vitry Sur Seine, France

[2] Sanofi, Dept Biol Sci, F-94403 Vitry Sur Seine, France

[3] Vitro Biol Genzyme Drug & Biomat, Waltham, MA 02451 USA

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2012年 / 423卷 / 03期

关键词：

tropomyosin-related kinase; TrkA; TrkB; X-ray structure; kinase insert domain; NERVE GROWTH-FACTOR; TYROSINE PROTEIN-KINASE; NEUROTROPHIC FACTOR; MOLECULAR-CLONING; PROTOONCOGENE PRODUCT; BINDING DOMAIN; RECEPTOR TRKB; HIGH-AFFINITY; NGF BINDING; EXPRESSION;

D O I：

10.1016/j.jmb.2012.08.002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The Trk family of neurotrophin receptors, which includes the three highly homologous proteins TrkA, TrkB and TrkC, is strongly associated with central and peripheral nervous system processes. Trk proteins are also of interest in oncology, since Trk activation has been observed in several cancer types. While Trk kinases are attractive oncology targets, selectivity might be more of an issue than for other kinases due to potential CNS side effects if several Trk kinases are simultaneously targeted. In order to address this issue, we present here the first structures of human TrkA and TrkB kinase domains and three complexes between TrkB and Trk inhibitors. These structures reveal different conformations of the kinase domain and suggest new regions of selectivity among the Trk family. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：439 / 453

页数：15

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